In for the Long Haul

In the 2008 New York City Marathon, runner #48068 was an architect from Alabama. He was also a liver transplant recipient. Robert Littleton, 37, of Birmingham, enjoyed running his first marathon. But nearly three years before that, he was racing against time.

Littleton, who had mild hemophilia A, contracted hepatitis C from a contaminated blood transfusion when he was a child. Years later, he was not prepared for the rapid progression to end-stage liver disease.

“Robert, your liver has completely stopped working. You have maybe two weeks to live. If you have not made final preparations, you need to do so at this time,” a doctor told him in late January 2006. On February 9, Littleton received a new liver.

For most liver transplant recipients, “the call” never comes early. It comes when a healthy liver is available, months or even years after being placed on a national transplant waiting list. For patients with hemophilia, the surgery is often complicated by hepatitis C and HIV. Facing the need for a transplant is daunting. Undergoing a liver transplant means enduring a lengthy recovery and a lifetime of anti-rejection drugs. But it also means being hemophilia-free.

Hard-working Organ

The liver is a workhorse. The largest gland in the body, it secretes bile, which breaks down fats; produces the protein factors that help the blood clot; creates lymph; and produces cholesterol. The liver metabolizes carbohydrates, fats, proteins and hemoglobin, converting them into substances the body needs. It is a storage site for glycogen, an energy source; it also stores certain vitamins and iron. The liver detoxifies drugs, helps the body fight infection and regulates the balance of some hormones.

Situated below the diaphragm and protected by the ribs, the liver is composed of lobes subdivided into lobules. It is the only internal organ that can regenerate itself.

Hep C and HIV: Destructive Duo

In the bleeding disorders community, there is a cutoff—those born after the early 1990s escaped the HIV and hepatitis epidemics. By then, blood donations were routinely screened for harmful viruses. However, a sizable number of adults in this community—approximately 40%—are co-infected.

HCV causes liver cells, or hepatocytes, to become inflamed. Continual inflammation and liver cell death lead to scar tissue formation. The degree of scar tissue, called fibrosis, is a measure of liver damage. The more fibrosis, the less the liver can function. Eventually it becomes cirrhotic, leading to end-stage liver disease or liver failure. “Hepatitis C is the leading indication for liver transplantation in the US,” says Kenneth Sherman, MD, PhD, Gould Professor of Medicine and director of the Division of Digestive Diseases at the University of Cincinnati College of Medicine. He is a member of the National Hemophilia Foundation’s (NHF’s) Medical and Scientific Advisory Council (MASAC).

Despite its lengthy job description, the liver is vulnerable. Irreversible damage can be done via drug and alcohol abuse and exposure to toxins and viruses. “Your immune system may be unable to deal with a multiplicity of insults,” says Margaret Ragni, MD, MPH, professor of medicine at the University of Pittsburgh and director of the Hemophilia Center of Western Pennsylvania. She is also a member of MASAC. Alcohol, hepatitis B and aging increase the risk of end-stage liver disease by factors of 4, 3 and 1.5, respectively, she says. “If you have hepatitis C virus [HCV] and HIV infection, HIV increases your risk 3.7-fold for end-stage liver disease,” says Ragni.

The mechanisms by which HIV accelerates liver damage are becoming clearer. Preliminary results from a study Ragni is leading indicate that HIV increases the body’s production of cytokines, chemicals that orchestrate repair. “But that repair response may become too active, to the point where it causes fibrosis and damage,” she says. HIV may directly infect stellate cells, which form scar tissue, and hepatocytes. The effects of direct and indirect (cytokine-mediated) damage are under active investigation.

Patients treated with highly active antiretroviral therapy (HAART) show promising results. In a study of 157 men with hemophilia and HIV/HCV co-infection published in Haemophilia in March 2009, Ragni and colleagues demonstrated that the men treated with HAART did not advance to end-stage liver disease for 30.3 years, compared with 20 years in the untreated group. The rate for HAART-treated men was equivalent to what men who were HIV-negative experienced. “Blocking HIV’s effect by treating with antiretroviral therapy can make a huge difference. It will slow down liver disease,” Ragni says.

The most effective treatment for ridding the body of HCV is a combination of two drugs: interferon and ribavirin. Patients must weigh their extreme side effects—from mood changes to depression, fatigue, flulike symptoms and headaches—against the final outcome. “The drugs lead to a sustained viral response and loss of detectable virus in upward of 50% to 60% of patients who are HIV-negative,” says Ragni. “The rate is lower, though, for patients who are HIV-positive.”

Littleton tried two rounds of the medications. The first time, he was pursuing a bachelor’s degree in architecture at Auburn University in Albany, Georgia. “I felt tired all the time. I had severe mood swings. My attitude changed,” Littleton recalls. He cleared the virus, but relapsed after 90 days. During the second round, he used pegylated interferon—a longer-lasting form. Once again, his body cleared the virus, but only temporarily. “You can imagine the elation,” Littleton says. “My whole life was changing.” Those words would soon take on a darker meaning.

Subtle Symptoms

Since liver disease can progress slowly, patients can miss or dismiss symptoms. “I had a lack of energy and moderate weight gain,” says Littleton of his advancing hepatitis. But he was busy working and going to college, so he ignored the signs. Therein lies the rub. “Often, liver disease is asymptomatic until it progresses to the very end stage,” says Ragni. She is a proponent of liver biopsy. “It is the gold standard for determining how much fibrosis is present in the liver.”

Michael O’Connor, 49, a retired radiation oncology physicist in Tempe, Arizona, and president of NHF’s Board of Directors, could not dismiss the symptoms of ascites. “I would gain 18 to 20 pounds from the water I was retaining,” he says. “I would blow up like a balloon.” Weekly, up to seven liters of fluid were extracted from his abdomen.

O’Connor’s liver was becoming decompensated, unable to rebound from damage. The scarring from cirrhosis thwarts circulation, causing the blood vessels in the liver to develop hypertension, or high blood pressure. This can result in an enlarged spleen and creation of ascitic fluid in the abdomen. Varicose veins can develop in the esophagus or stomach, where they rupture easily, causing bleeding.

Another symptom is hepatic encephalopathy, or altered brain function. It results when the liver cannot break down toxins, such as ammonia. As the ammonia builds up, it penetrates the brain, causing mental disturbances. O’Connor experienced this firsthand. “I was so confused at times, you could have mistaken me for being flat-out drunk,” he says.

Jaundice is a more familiar sign of liver disease. “The nurse told me to come meet this yellow man,” one of the doctors said to Littleton when he was hospitalized. His liver could not break down bilirubin, a yellowish pigment in hemoglobin, which then was deposited in his skin.

Role of the Hepatologist

Liver specialists believe earlier intervention with patients is needed. “It’s better to have a hepatologist at a transplant center involved before someone decompensates,” says Sherman.

The hepatologist performs the liver workup, a weeklong series of tests that is necessary before the patient can be placed on a transplant waiting list. The tests determine the causes of the liver disease, assess complications, and coordinate the evaluation of other potentially diseased organs, such as the heart, lungs and kidneys.

In addition, the hepatologist oversees the evaluation of drug and alcohol dependence, the psychiatric condition of the patient, the support network at home and the patient’s insurance coverage and finances.

Patients with hemophilia usually pass muster. “In many ways, people with hemophilia and advanced liver disease tend to be excellent candidates,” says Sherman. Most have established family support networks and fewer incidences of alcohol abuse, he says. “The other co-morbid conditions have often been better managed because of regular healthcare given at a comprehensive hemophilia treatment center under the direction of expert hematologists.” Patients with severe hemophilia pay more for the tests, he says, because of factor coverage.

Preparing for a transplant also means financial planning. “Liver transplant is not only a very expensive process in the workup, evaluation and actual transplantation, but in terms of maintaining the liver for the rest of the patient’s life,” Sherman says. He estimates it could cost $100,000 while waiting for the transplant, plus $150,000 to $200,000 for the surgery. Factor in another $10,000 to $15,000 per year for life for medications and tests.

Understanding the National Transplant Network

In the United States, the United Network for Organ Sharing (UNOS) coordinates all transplants. According to its Organ Procurement and Transplantation Network (OPTN) statistics, 5,273 liver transplants were performed in 2008. More than 16,000 people are on the waiting list. Because the demand exceeds the supply, UNOS created a system to rank patients. The urgency of the need for a liver transplant is determined by the Model for End-stage Liver Disease (MELD) score. (See sidebar, “The Waiting Game.”)

In 2002, O’Connor, who contracted HIV from contaminated factor products in 1982, was faced with a liver transplant. “Not many sites were doing HIV-positive transplants then,” he says. One of those was the Mayo Clinic in Jacksonville, Florida, which received a relatively large number of livers. O’Connor was tested there.

Being listed in multiple regions can often determine a patient’s outcome. “The pre-evaluation testing puts you through the wringer, but in some cases, you can be listed at multiple sites,” O’Connor says. “If I had been listed here in Arizona, I might have died waiting for a liver.”

Patients researching transplant centers should note survival rates. The national average for the one-year survival rate is 83.4%, according to OPTN; the national average for the five-year survival rate is 67.4%. Find out how long the program has existed and how many liver transplants it has performed. A center that participates in NIH-funded studies follows NIH protocol and contributes invaluable data.

Waiting for a liver means waiting for someone to die—that is, unless you have a living donor. (See sidebar, “Living Donor Decision.”)

Littleton’s room at the University of Alabama at Birmingham Hospital overlooked the emergency helipad. When a helicopter landed, his stepmother said, “They have a lot of accidents during this time. Maybe an organ will come for you.”

“How could I pray for the death of another person?” Littleton asks with grim candor. Then prayer revealed to him an acceptable approach. “We can’t pray for death or an accident,” Littleton told his family. “We need to pray for a gift.”

Both Littleton and O’Connor felt calm while awaiting their transplants. Even though O’Connor’s family was “devastated” after the first liver failed, he was not. “I took a more positive attitude—that the second transplant would happen.” Littleton had a similar outlook. “I never felt like my life was in jeopardy, although it was. I guess it was just brazen confidence and the belief that it wasn’t my time.”

Liver Transplant Surgery

The liver transplant surgeon, accompanied by a team of physicians, removes the damaged liver, disconnecting its blood supply and bile ducts. Then the new liver—either a whole liver from a deceased donor or a portion of a liver from a live donor—is placed in the cavity, and the blood vessels and ducts are reattached.

“This is a challenging technical operation, because the blood supply flowing to the cirrhotic liver is under high pressure,” says Peter Stock, MD, transplant surgeon at the University of California-San Francisco Medical Center. Other complications include previous scar tissue formation and the degree of cirrhosis. “If there was previous surgery, the scar tissue can be extreme. Since the cirrhotic liver is inflamed, it tends to adhere to its surroundings.” Stock estimates that a straightforward first-time liver transplant takes about five to six hours. A second surgery can increase the time, taking more than 10 hours in some cases.

For the surgery to be successful, timing is everything. “If we can get the organ in an expedient amount of time, prior to significant deterioration of the patient’s condition, there is a faster recovery and better chance for success,” Stock says.

Long and Winding Recovery Road

Most patients are out of the hospital within two weeks. “As soon as the liver starts working and making protein—we assess its function by measuring clotting factors—the patient is released,” Sherman says. The follow-up includes weekly blood tests and on-call availability if complications develop.

“In the first year, there are frequent callbacks because of abnormal liver tests, representing either rejection or hepatitis C, which are quite common,” says Sherman. If not cleared prior to the transplant, HCV presents management problems later, he says. Reservoirs of the virus hide in the body, always infecting the new liver after transplantation. In the majority of patients, HCV infection progresses slowly. “There is advanced disease present in about 50% of patients about 10 years out,” he says. “A small number of patients have rapidly progressive liver disease, however, and may lose the organ within one to two years.”

Acute rejection occurs in many patients, most during the first one to two years after the transplant. Often a liver biopsy or other tests are recommended. “If the patient says, ‘I can’t get a ride,’ or ‘I’ve had enough of hospitals,’ he could lose that organ a week later,” Sherman warns.

“It’s absolutely critical that patients be very highly ­motivated,” asserts Sherman. “There’s not much margin for error in the first six months to a year afterward.”

Patients take anti-rejection drugs for the rest of their life. The highest doses are given during the first three months after the transplant. Side effects include increased risk of infection, nausea/vomiting, tremors, unwanted hair growth and risk of kidney injury. Eventually the body adjusts. “You can then reduce the immunosuppressive agents, which reduces the side effects,” Sherman says.

Back-to-back liver transplants slowed O’Connor’s recovery. “It was a long process,” he recalls. “I had lost so much muscle mass that I couldn’t get out of a chair by myself.” Narcotic pain medications deterred him from driving. Still, he performed some of his duties as president of the Hemophilia Association of Arizona and attended summer camp.

A family support system is crucial after liver transplantation. O’Connor’s wife, Debby, took family leave, then quit her job. “It’s very important that you have somebody like I did to be an advocate and participate in your care,” says O’Connor. Debby acted as a liaison with his doctors, coordinating his appointments and medications. At times, O’Connor was depressed. “When I was down, I didn’t want to do anything. That’s when I needed Debby.”

“Although I was back to work within 30 days, I was tired,” says Littleton. Inactive and with an increased appetite, Littleton gained weight during his yearlong recovery. Then running came into the picture.

“I used running as a vehicle to make me healthy,” Littleton says. He shaved 70 pounds off his 5'9" frame training for races. In February 2008—nearly two years after his liver transplant—Littleton ran a half-marathon in Birmingham. Two weeks later, he ran one in Georgia. Then Littleton set his sights higher. He entered the lottery for the New York City Marathon and was accepted.

Hemophilia: Undone

The bonus of a transplant is that the new liver produces the protein factors that clot the blood. The patient enters the surgery with hemophilia and leaves without it. Littleton noticed the difference immediately. “Before, brushing my teeth and shaving could cause bleeds,” he says. Now he can do both without complications.

For O’Connor, the transplant was life-changing­. “For 43 years, I lived as a person with hemophilia, making sure I had factor in the house or when I traveled.” After the surgery, he says, it was like somebody flipped a switch. “Now I don’t have to start an IV or time things,” O’Connor says. “It changed my whole thought process—my identity changed. As far as I’m concerned, I no longer have a bleeding disorder, but I will always be a person with hemophilia.”

Littleton is fulfilling a promise he made to God when he was waiting for a new liver. “I prayed, ‘God, if this is my time, I’m ready to go. If not, I want to make a difference.” His marathon training is the subject of motivational talks he gives to children awaiting transplants. “I’ve been spared for a reason. I want to tell my story and encourage others.”